Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model
Satish N Dighe, Eugenio De la Mora, Stephen Chan, Srinivas Kantham, Gawain McColl, Jared A Miles, Suresh Kumar Veliyath, B Yogi Sreenivas, Zeyad D Nassar, Israel Silman, Joel L Sussman, Martin Weik, Ross P McGeary, Marie-Odile Parat, Xavier Brazzolotto, Benjamin P Ross
COMMUNICATIONS CHEMISTRY | NATURE PUBLISHING GROUP | Published : 2019
The development of polyphenols as drugs for Alzheimer’s disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Aβ) fibrillation, protect against Aβ42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Aβ42, with potencies similar to rivastigmine and natural polyphenols. The results suggest that a te..View full abstract
Awarded by DGA/SSA BioMedef
The following financial support is gratefully acknowledged: UQ School of Pharmacy funding (M.-O. P. and B.P.R.); and DGA/SSA BioMedef contract PDH-2 NRBC-3-C-3201 (X. B.). S.N.D., S.C., S.K., J.A.M., S.K.V., B.Y.S. and Z. D.N. thank UQ and the Australian Government for PhD scholarships. S.N.D. thanks UQ for a GSITA travel grant.